Objective: A major objective of this proposal is to train Dr. Sowers to become an independent translational neuroscientist in the VA system. To accomplish this, he has prepared a research plan that will allow training in state-of-the-art optogenetic techniques to address a major issue facing Veterans, post-traumatic headache. Veterans returning from active duty are at an increased risk for post-traumatic headache that includes migraine. U.S. military personnel screened within 90 days of returning from a one-year combat tour in Iraq had 2-4 times the rate of migraine compared to civilians. One debilitating aspect of post traumatic headache is concurrent photophobia which can negatively affect Veterans daily lives. Interventions and treatments for post- traumatic headache and photophobia remain inadequate due to a poor understanding of the relevant neuroanatomical correlates. This proposal aims to identify brain regions that are directly involved with the development of post-traumatic headache and photosensitivity and test pharmacological agents to mitigate light sensitivity. As a starting point we plan to focus on areas implicated in light aversion and modulated by the neuropeptide calcitonin gene-related peptide (CGRP). Our findings will overcome two major hindrances in the development of future treatments for Veterans with traumatic brain injury (TBI) by determining: first, which brain regions are sufficient to induce photophobia, and second, whether these regions are necessary for the development of TBI induced photophobia. The results from these studies will guide future innovative therapeutic interventions, such as deep brain stimulation and transcranial stimulation, for the treatment of this debilitating chronic condition of TBI. This stuy will be aided by clinical interactions with his multidisciplinary mentoring team, two of which are practicing psychiatrists within the VA system, as well as a neuro-ophthalmologist. Dr. Sowers will have access to a large TBI population at the Center for the Treatment and Prevention of Visual Loss. The training plan will also take advantage of interactions with clinicians and basic scientists in the VA Center. Moreover, Dr. Sowers' mentor has ongoing collaborations with two pharmaceutical companies (Alder and Eli Lilly) that will facilitate the translation of the expected findings to clinical trials. These clinical perspectives will not only aid with the applicant's traning, but will also focus the research plan on a fast translational timeframe. Methods: We have established a pre-clinical blast-induced light-aversion model as an objective indicator of post-traumatic headache. In Aim 1, we will use optogenetic applications to target specific brain regions we hypothesize to be involved with the development of post-traumatic headache. In Aim 2 we will use pharmacological manipulation of CGRP to alleviate post-traumatic headache in C57BL/6J wild type mice. Expected results: This proposal will have three main outcomes: 1) It will establish the applicant as an expert in pre-clinical TBI models that are closely linked to translational testing of novel therapeutics. 2) It will significantly advance our understanding of the neuroanatomy underlying post-traumatic headache and photophobia by identifying brain regions that could be targets for specific deep brain stimulation or transcranial stimulatory treatments. 3) The proposed work will benefit Veterans by identifying future pharmacological treatments to ameliorate post-traumatic headache.